Should Iron Be In Your Multivitamin?

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Should Iron Be In Your Multivitamin?

 

A Literature Review and Conclusions

By Donald P. Goldberg, R.Ph

Willner Chemists

 

Introduction

 

For most people, iron should be included as part of the daily

multivitamin supplement program. There are exceptions, and those

will be explained below. As is the case with so many things, iron

has two sides, and we have to decide whether its advantages outweigh

its disadvantages.

 

When evaluating the question of iron supplementation, we have to

remember that iron deficiency is one of the most common nutritional

shortfalls in the United States today.1 We have to remember, as

well, that we can be deficient in iron, and may be unaware of it.

 

" The initial stage of iron deficiency usually has no symptoms. It

occurs when the body's iron stores are depleted or exhausted, a

condition reflected by a drop in the blood's iron levels and an

increase in transferrin-a protein that transports iron through the

blood stream.

As the iron supply to the bone marrow dwindles, so

does the marrow's ability to produce healthy red blood cells, which

require iron.

If the iron balance worsens, full-blown iron-

deficiency anemia-characterized by low hemoglobin levels-can

gradually develop. Since iron is an essential component of

hemoglobin, a shortage of iron can impair the transport of oxygen

from the lungs to the body's cells; as a result, work performance

will be impaired.

 

" It can take months or even years for symptoms of iron deficiency-

such as weakness, shortness of breath, paleness, poor appetite, and

increased susceptibility to infection-to become evident. These

usually disappear when iron stores are rebuilt. " 1

 

On the other hand, many people with " iron-overload " , or

hemochromatosis, often have no symptoms

 

 

 

Iron: Why Is It Essential?

 

All cells in the body contain iron. It plays a vital role in many

biochemical reactions. Perhaps its most important role is related to

its incorporation in hemoglobin, the oxygen-carrying protein that

gives blood its red color, and in the myoglobin in muscle.

 

Myoglobin, like hemoglobin, is a transporter of oxygen-it supplies

oxygen to the muscle cells for use in the chemical reaction that

results in muscle contraction. Low iron intake over a long period of

time can gradually lead to a depletion of iron stored in the body.

 

This is of special concern when there is loss of blood, as in

menstruation. " Iron is therefore the main determinant of how much

oxygen reaches and is used by all body tissues, including the brain,

muscles, heart, and liver. " 15

 

" Iron is also necessary for collagen synthesis. Iron is found in the

brain as a cofactor in neurotransmitter synthesis for serotonin,

dopamine, and noradrenalin, which are known to regulate

behavior. " 14 " Iron strengthens the immune system and increases

resistance to colds, infections, and disease. " 15

 

As the iron supply to the bone marrow dwindles, so does the marrow's

ability to produce healthy red blood cells, which require iron. If

the iron deficiency continues, full-blown iron-deficiency anemia,

characterized by low hemoglobin levels, can develop.

 

" It can take months or even years for symptoms of iron deficiency-

such as weakness, shortness of breath, paleness, poor appetite, and

increased susceptibility to infection-to become evident. These

usually disappear when iron stores are rebuilt. " 1

 

 

 

Why is Iron Supplementation Necessary?

 

According to Murray, " Although the human body contains only about

0.004 percent iron, it is one of the most significant elements in

nutrition and consequently very necessary to life. Iron deficiency

is said to be the second most common nutritional problem in the

United States, following obesity. " 13

 

" Without an adequate iron supply, people are at risk for developing

a variety of symptoms, such as reduced work capacity; more rapid

build-up of lactic acid in exercising muscle; irritability and

apathy; lower resistance to infections; spoon-shaped, thin nails;

and pale nail beds.

 

It is difficult to get sufficient iron from the

diet because all food sources are not all equal in value. For

example, spinach is rich in iron, but the mineral is bound by

chelates and takes it out of the body before it can be properly

absorbed.

 

Other chelates include tannins in tea; phytates in whole

grains, brans and soybeans; polyphenols in coffee; and phosvitin in

egg yolk 13. "

 

" Unusual food cravings are associated with an iron deficiency.

Cravings for ice, starch, clay, and other nonfood items have been

attributed to a deficiency. Children who are deficient have a

tendency to hperactivity, decreased attention span, and lower IQ's.

This conditions can be helped if iron amounts are restored. " 14

 

" Iron is the most important mineral for the prevention of anemia

during menstruation. Iron may also be beneficial in the treatment of

leukemia and colitis. Plummer-Vinson syndrome is cured with iron.

This disease can lead to esophageal and stomach cancer.

Candida and

herpes simplex are helped with sufficient levels of iron if

deficient already. Iron-requiring proteins generate oxygen radicals

that kill bacteria like the ones in mother's first milk. Muscle

weakness and exercise endurance are improved with iron. Both cardiac

and muscular performance are included. " 14

 

Are conditions such as anemia, impaired immune function and fatigue

the only examples that optimal levels of iron intake is important?

Not at all.

 

It has been know for many years that there is a connection between

low iron levels and " restless legs syndrome. "

 

A recent study at Royal Liverpool University concluded that " Iron

deficiency, with or without anemia, is an important contributor to

the developement of Restless Legs Syndrome in elderly patients, and

iron supplements can produce a significant reduction in symptoms.21

 

A recent report in Tufts University Health & Nutrition Letter lends

further support to this relationship.22

 

" Up to five percent of the population has restless leg syndrome--an

urge to move the legs, often accompanied by a creeping, crawling, or

tingling sensation, which worsens when the body is inactive and

thereby causes significant sleep disruptions.... But studies have

indicated--and clinicians at various sleep disorders centers have

found--that in patients with low levels of iron, iron pills may be

all it takes to relieve symptoms and allow for a good night's

sleep. "

 

They go on to point out that the " iron deficit doesn't have to be

very large...research has found that even people whose serum

ferritin falls between 20 and 50 and therefore technically have a

normal level can sometimes benefit from iron supplementation. "

According to Dr. Ehrenberg, of the New England Medical Center Sleep

Disorders Unit, " There's even a small percentage of people with

serum ferritin levels of 50 to 100 who respond " to iron

supplementation with reduced restless leg symptoms.

 

 

 

Why is Iron Supplementation Discouraged by Some?

 

It has become popular to warn about the dangers of iron. There is

the author who " was forced to give up her career after being

stricken with an unidentified disabling illness.

 

After 12 years of

going from doctor to doctor, she was finally diagnosed with iron

overload and elevated levels of aluminum, lead and copper...

Following her treatment and recovery, she began researching the

scientific literature on the subject of iron overload, a potentially

lethal, but underdiagnosed and undertreated medical condition. Her

book... " 4

 

Then, you have a occasional study that implicates iron with

problems, such as heart disease. Probably the most often quoted

study of this type is one published in 1992, usually referred to as

the Finnish study.5

 

The fact that this study could not be duplicated in two subsequent

studies seems to have little effect on those who persist in looking

to blame iron for various health ills.6,7

 

Dr. Steve Austin,9 for example, is quick to point out that " this is

not so with all such reports. For example, in the November 18, 1997

issue of Circulation, a prospective study found ferritin to be

the `strongest risk predictor of overall progression of

atherosclerosis. " 8

 

And Dr. Austin follows up with another article

highlighting a study in Greece that claims to show a relationship

between dietary iron intake in men and increased risk of heart

disease.10

 

A study of Finnish men published, 1992 made headlines when it

offered evidence that even " normal " levels of iron stored to the

body may increase the risk of a heart attack.

 

Is iron one more risk

factor men should worry about? Not at this point For one thing, a

high level of iron may be a marker for some other factor that's the

real culprit

Also, the men in the study already had relatively high

iron levels compared to Americans, as well as a high incidence of

heart attacks—among the highest in the world.

 

Another point: only a

small amount of dietary iron is absorbed by the body, and that

amount is affected by many factors including other foods you consume

and your body's needs Thus, an iron-rich diet doesn't necessarily

lead to iron overload,

 

At this point, there is not nearly enough evidence supporting the

link between iron and heart disease Until a stronger case is made,

healthy men should continue to eat foods that supply their daily

requirement of iron.1

 

The problem with studies like this is that they deal in

possibilities, not facts. In other words, it is sometimes difficult

to determine whether we are looking a the cause, or the effect.

 

For

example, a patient with high iron levels may have high levels

because he is a long-time heavy meat eater. Is the fact that he is

at high risk of heart disease a function of the high level of stored

iron, or is the iron merely a coincidental result of the heavy meat

diet, with other factors related to animal fat intake the real

culprit?

 

Another problem with iron is that iron storage diseases such as

hemochromatosis are more common than previously thought.

 

 

 

Iron and Lipid Peroxidation

 

All of the functions that iron performs in the body are based on its

ability to donate and accept electrons, i.e. participate in

oxidation-reduction reactions.

 

It is this characteristic that makes

iron a highly reactive and potentially toxic nutrient. This can be

said for many of the powerful antioxidants found throughout

biological systems.

 

It is now commonly accepted that the oxidation of low-density

lipoprotein (LDL) results in the modified LDL being taken up more

readily by macrophages, which results in the development of the

fatty streak, the initial lesion of atherosclerosis.

 

Iron, as well

as copper, has been shown to promote the modification of LDL in

vitro and is suspected of participating in these reactions in the

body. Is this really a problem?

 

Although many studies provide convincing evidence that iron does

participate in free radical reactions and the modification of LDL

under experimental conditions, it remains unknown what conditions

must exist in the body for iron to participate in these reactions.

 

 

Normally, the body takes great care in keeping iron in a nonreactive

state. For example, the potential for free iron to exist in serum is

low, because the iron transport protein, transferrin, is only

approximately 30% saturated with iron under normal conditions. This

allows for a large capacity to deal with changes in iron

concentration within the serum pool (Beard, 1993).

 

Only as

transferrin saturation approaches 100% does iron become available to

participate in free radical generation under normal conditions.

However, free iron has been observed in the plasma of

hemochromatosis patients whose transferrin saturation was much less

than 100% (Aruoma et al., 1988).

 

 

This may be indicative of an

inability of transferrin to bind iron sufficiently in

hemochromatosis patients. After delivery of iron to the cell, the

transferrin-iron complex enters the cell through receptor-mediated

endocytosis. Once in the cell, iron is utilized by iron-dependent

systems, and any surplus iron is stored tightly chelated in a

nonreactive state in ferritin and hemosiderin (McCord, 1991).

 

Ferritin, because of its iron-binding properties, is a strong

cytoprotective antioxidant (Balla et al., 1992; Gutteridge and

Quinlan, 1993). Moreover, pools of dormant ferritin mRNAs exist in

the cytoplasm which can be rapidly translated to yield a large

number of ferritin subunits in response to increases in cellular

iron (Munro, 1993). This prevents the accumulation of iron within

the cytoplasm and the peroxidation of cell lipids, DNA, and various

proteins.

If the storage capacity of ferritin is exhausted, excess

iron is then stored in the form of hemosiderin, which is a more

insoluble iron deposit that is not readily available to the organism

(Welch, 1992). Therefore, the association of iron with transferrin,

ferritin, and hemosiderin prevents iron's participation in

undesirable reactions thought to be involved in the development of

atherosclerotic lesions.11

 

Nevertheless, extreme levels of iron in the body can result in

myocardial tissue damage as evidenced by the clinical manifestation

of heart disease in hemochromatosis and other iron-storage disease

patients.

 

Furthermore, the ability of iron chelators to reduce

injury to heart tissue immediately after a cardiac arrest

demonstrates that iron does contribute to heart damage age after a

heart attack has occurred (Babbs, 1985; Bernier et al., 1986;

Williams et al., 1991).

 

However, it must be recognized that these

are extreme conditions that do not implicate normal iron status as a

risk factor for atherogenesis in healthy individuals.11

 

Free radicals are generated in the body as part of normal cellular

processes. For instance, the body utilizes free radicals as a way to

kill invading bacteria.

 

" Fortunately, free radical scavenger

systems, such as superoxide dismutase and glutathione peroxidase,

exist to prevent or terminate the undesirable accumulation of free

radicals generated in these situations.

Consequently, nutritional

status of nutrients known to have antioxidant functions or integral

roles in free radical scavenger systems (i.e. copper, zinc,

selenium, carotenoids, and vitamins A, E, and C), is important to

consider.

It may be a deficiency of these nutrients that creates an

opportunistic environment that promotes atherosclerotic sclerotic

lesions and not just the presence of transitional metals such as

iron (Ames et al., 1993; Manson, 1993... " 11

 

The Finnish Study

 

We have already alluded to the often quoted Finnish Study (Salonen,

et.al, 1992. They found that eastern Finnish men with serum ferritin

levels greater than 200 µg/L had a 2.2-fold risk-factor-adjusted

risk of acute myocardial infarction (AMI) compared with men with

lower serum ferritin levels.

This was a prospective 3-year followup

study of 1931 eastern Finnish men aged 42, 48, 54, and 60 years who

had no previous history of heart disease upon entry into the study.

 

Although these results indicate that serum ferritin in the

uppernormal range was a risk factor for AMI in the population

studied, it has been questioned whether the data can be readily

extrapolated to other groups (Beard, 1993). The nutritional patterns

of a similar group of eastern Finnish men were reported by Ihanainen

et al. (1989), who collected nutritional data on 1157 eastern

Finnish men aged 54 years.

 

 

Results of this analysis showed the

consumption of vegetables in this population to be low (110 g/day),

whereas coffee (586 g/day) and fat intake (40% of energy intake)

were high.

 

Intake of saturated fat was four times greater than that

of polyunsaturated fat, and dairy product consumption consisted of

70% butter.

 

Meat intake comprised mainly sausage (39%), beef (37%),

and pork (21%), and the mean daily intake of cholesterol was 480 mg.

The average intake of nutrients known to protect against lipid

peroxidation, such as vitamin E, copper, and selenium, was below

recommended dietary allowances.

 

The authors of this study indicated

their findings were consistent with other studies that have

evaluated the diet of the Finnish population (Uusitalo, 1987;

Seppanen, 1981).

 

The enormous range in serum ferritin levels (10-2270 µg/L) in these

subjects is a strong indicator that the recessive hemochromatosis

gene was present in this cohort and possibly driving the observed

association between stored iron and AMI (Beard, 1993). Other

explanations for such high serum ferritin levels include the

presence of undetected conditions known to elevate ferritin levels,

such as liver disease and cancer (Finch et al., 1986).

 

It is these

population attributes and the fact that eastern Finnish men have the

highest recorded incidence and mortality from CHD (Keys, 1980) that

makes extrapolation to other populations difficult. Moreover,

although ferritin was found to be a significant risk factor for AMI

with a relative risk of 1.03 in this population, several other

factors were also found to be statistically significant and have

greater relative risks for AMI than serum ferritin. For instance,

serum copper, serum apolipoprotein B, and diabetes had approximately

600, 400, and 250 percent greater relative hazards of AMI than

ferritin, respectively. The weaker association of ferritin to AMI

compared with these other factors may be due to ferritin's ability

to sequester iron in a nonreactive form (Balla et al., 1992;

Gutteridge and Quinlan, 1993).11

 

Does Iron Accumulate With Age?

 

Much of the concern about iron in supplements arises from the belief

that in men, especially sedentary men, there is little means by

which stored iron can be lost, and therefore it continues to build

up over the years, eventually reaching " overload " levels. This may

not be the case:

 

The hypothesis that iron stores are related to the risk of

cardiovascular disease (CVD) arose in part from the observation that

the incidence of CVD increases with age in men and in postmenopausal

women (Kannel et al., 1976; Gordon et al., 1978). Other studies

reported that iron stores also accumulated with age in men and in

postmenopausal women (Cook et al., 1976). Thus, Sullivan

hypothesized that the two observations were related (Sullivan,

1981). However, NHANES II and NHANES III pilot study data appear to

indicate that iron may not accumulate with age. Figure 1 represents

data of mean serum ferritin values of non-hispanic white (NHW) males

and females at various ages from NHANES II and NHANES III pilot data

of all persons measured. As can be observed from the graph, ferritin

values do not increase appreciably with age in men, but values do

increase in women as they pass through menopause. Interestingly,

Solonen et al. (1992) reported that serum ferritin concentrations

decreased after 48 years of age in the eastern Finnish men they

studied.

 

The recent proposal of a setpoint theory, whereby iron stores

regulate iron absorption to maintain an individual's preset iron

stores, challenges the idea that iron stores accumulate with age.

 

Garry et al. (1992) proposed the setpoint theory after assessing

iron stores in 27 postmenopausal healthy women who donated 5 units

of blood over 1 year compared with 59 controls. Iron stores in the

control group did not change over 2 years, despite large differences

in baseline iron stores and similar dietary iron intakes. The

authors speculated that a setpoint exists for individual iron stores

which is under genetic control. If this is so, it would be difficult

to increase iron stores through diet or supplementation when iron

stores are at or near an individual's predetermined setpoint. Gavin

et al. (1994) further investigated the setpoint theory in 21

individuals selected from the same study population as that used by

Garry et al. (1992). Iron absorption changed according to changes in

baseline iron stores, and 70% of the variation in iron absorption

was explained by the changes in iron stores from baseline,

indicating an adaptation to the level of depletion of iron stores

below the setpoint. If iron stores are regulated as described by the

setpoint theory, iron stores would not be expected to increase with

age.

 

Is Low Iron Protective Against Heart Disease?

 

If high iron levels are related to increased risk of heart disease,

as some claim, it would be logical to assume that low levels would

infer a protective effect. But this does not seem to be the case.

 

Within the iron/heart disease paradigm, it would be predicted that

other indicators of iron deficiency, such as a low transferrin

saturation (serum iron divided by total iron binding capacity x

100), would indicate protection against heart disease, because a low

transferrin saturation would possess potent antioxidant activity. As

indicated by Beard (1993), determination of transferrin saturation

could provide a better understanding of the association of iron and

heart disease. Magnusson et al. (1994) studied 2036 men and women

between the ages of 25 and 74 years who were participating in a

large epidemiological study.

It was found that increased total iron

binding capacity (TIBC) was protective against MI, whereas serum

ferritin had no significant association.

 

It was also observed that

transferrin saturation had less predictive power for MI than did

TIBC. Another study was recently completed on 46,932 subjects whose

serum iron and TIBC were measured and who were followed for a 14-

year period (Baer et al., 1994). During the followup period, 969 men

and 871 women had an AMI-related hospital stay. Results did not show

iron deficiency, as indicated by low transferrin saturation, to be

protective against heart disease. Liao et al. (1994) examined data

from the 4237 respondents of NHANES I aged 40-74 years (1827 men and

2410 women). Hemoglobin, serum iron, and the total iron-binding

capacity of transferrin (TIBC) were determined. During the 13-year

followup, 489 persons had an AMI, and 1151 developed CHD.

 

Hemoglobin, hematocrit, and TIBC were not associated with the

incidence of MI or CHD. Transferrin saturations in both men and

women who developed CHD were lower than in those who did not, and

each 10% increase in transferrin saturation was associated with a 9%

decrease in risk of CHD among men and a 12% decrease among women.

 

The authors caution that these results are only suggestive, because

the influence of diurnal variation and other factors such as

inflammation and malignancy were not monitored or controlled. Sempos

et al. (1994) also assessed the association between the risk of MI

and serum transferrin saturation in 4518 men and women who were part

of NHANES I. The risk of CHD was not related to transferrin

saturation levels, and results indicated there may even be an

inverse relationship. 11

 

Other Research On Iron and Cardiovascular Disease

 

As briefly mentioned earlier in this report, there is a considerable

body of research that does not support the proposed connection

between iron and heart disease. The following summary was presented

in the article by Proulx and Weaver.11

 

Since the publication of the Finnish study by Salonen et al. (1992),

many other studies that have investigated the association of iron

and heart disease have been completed. Researchers from the

Karolinska Institute in Stockholm, Sweden, conducted a case-control

study to investigate the effect of iron on the risk of AMI at a

young age (Regnstrom et al., 1994). Ninety-four men who experienced

an MI before the age of 45 years were compared with 100 age-matched

population controls. There was no association between the measure of

iron status and severity of coronary atherosclerosis, suggesting

that iron stores were not a risk factor for premature coronary

atherosclerosis. In another investigation, 252 patients between the

ages of 29 and 84 who were admitted for cardiac catheterization to

Duke University Medical Center also had their blood analyzed for

serum ferritin, total iron, TIBC, and transferrin along with

lipoprotein profiles (Lin et al., 1994). When coronary artery

disease (CAD) risk factors (age, sex, body mass index, lipid-

lowering drugs, smoking, and special diet) were controlled for, no

relationship between indicators of iron status and extent of CAD was

found. A prospective study of plasma ferritin and risk of MI in 238

men with MI and 238 controls matched for age and smoking found that,

after adjustment for other coronary risk factors, men with serum

ferritin levels greater than 200 µg/L had a relative risk of 1.1

(Stampfer et al., 1993). This suggests little or no increased risk

associated with normal ferritin levels. Aronow (1993) evaluated the

association between serum ferritin levels and CAD in 171 men and 406

women. The mean age of men (n = 74) and women (n = 172) with CAD was

82 years; that of men and women without CAD was 81 years. The mean

serum ferritin concentration was not significantly different between

men and women with and without CAD, indicating ferritin was not a

risk factor for CAD in these elderly men and women. Miller and

Hutchins (1993) selected 130 adult patients from 48,000 autopsy

records performed from 1889 to 1993 at Johns Hopkins University.

These patients were carefully matched for age, sex, and time of

death. Sixty-five of these had iron overload and 65 did not. The

researchers concluded that people with iron overload did not appear

to have significant amounts of CAD. Only 3 of the 65 patients with

iron overload had one coronary artery with 90% or more blockage.

 

Salonen et al. (1992) also reported that the intake of dietary iron

was strongly associated with the risk of AMI in eastern Finnish men.

However, Rimm et al. (1993) measured dietary iron intake through a

food frequency questionnaire during a 4-year followup of 45,720 men

aged 40-75 years with no previous history of heart disease. Eight-

hundred eighty cases of coronary disease were documented, and, after

adjusting for other risk factors, men with the highest intake of

iron had an insignificant relative risk of heart disease compared

with men with the lowest intake of iron. The relative risk of CHD

for each milligram increase in dietary iron was 1.0, indicating no

increased risk. Ascherio and Willet (1994) studied iron intake and

its association with coronary disease in 44,933 men aged 40-75 years

and found that higher intakes of heme iron were associated with

greater risks for MI but not dietary iron in general.

 

Is Lower Heart Disease Among Premenopausal Women Due To Lower Iron

Levels?

 

Based on the iron/heart disease theory, premenopausal women are

thought to have increased protection against heart disease due to

iron loss as a result of menstruation. If iron loss via menstrual

blood flow was responsible, those women who take oral

contraceptives, which decreases menstrual blood flow, would not

exhibit this protective effect. In fact, significant differences in

iron stores have been found between users and nonusers of oral

contraceptives (Frassinelli-Gunderson et al., 1985). But this does

not seem to be related to iron levels in the body.

 

Moreover, earlier studies found that current and discontinued use of

oral contraceptives was associated with an increased risk of heart

disease (Slone et al., 1981). Dr. Sullivan hypothesized that the

increased risk for CHD among oral contraceptive users was due to the

accumulation of iron (Sullivan, 1981). A recent study on the effects

of low-dose oral contraception on menstrual blood loss and iron

status found that menstrual blood loss was reduced by approximately

44% in women taking low-dose oral contraceptives (Larsson, 1992).

However, serum ferritin concentrations in these subjects remained

unchanged over the 6-month period of the study. Stampfer et al.

(1988) studied 119,000 women who were 30 to 55 years of age and

found that the use of oral contraceptive agents in the past did not

raise a woman's risk of heart disease. Because oral contraceptives

decrease menstrual blood loss and increase iron stores, it would be

expected that longer usage of oral contraceptives would be

associated with an increased risk. However, Stampfer et al. (1988)

noted that women who had previously used oral contraceptives for

more than 10 years had no increased risk. On the other hand, current

users of oral contraceptives did have an increased risk of CHD of

2.5, but this excess risk was observed predominately in smokers.

Porter et al. (1985) studied more than 65,000 women, 15 to 44 years

of age, who were healthy nonsmokers and found that no MIs occurred

in users of oral contraceptives. The 11 deaths due to CVD in the 6-

year period occurred in the women who were not using oral

contraceptives (Porter et al., 1987). The increased incidence of MI

in older users of oral contraceptives appears to be due to higher

doses of estrogen in the formulations taken by these women. Stampfer

et al. (1991) observed less benefit among women taking more than

1.25 mg of estrogen daily. In another study, an increased incidence

of heart disease was found only among older users who had other

known risk factors for heart disease (Mann et al., 1976). Mant et

al. (1987) analyzed results from a large cohort study in Britain and

found the risk ratio for MI in current users of oral contraceptives

was not increased, and no MIs were found in women who used

formulations with less than 50 µg of estrogen. Therefore, the

increased risk of heart disease that has been observed in women who

use oral contraceptives, past and present, appears to be strongly

associated with the dose of estrogen and smoking habits rather than

iron stores.11

 

Does Menopause Support the Iron-Heart Disease Paradigm?

 

If increased levels of stored iron was responsible for increase

heart disease, it would be expected that postmenopausal women would

have a remarkable increase in coronary heart disease, due to

posmenopausal amenorrhea. Indeed, there is an increase of CHD, but

iron may not be the real culprit. Instead, what may be in operation

in this case is the protective effect of estrogen.

 

However, this theory ignores the observed role of estrogen in the

decreased incidence of heart disease among women (Colditz et al.,

1987; Stampfer et al., 1991; Wolf et al., 1991). Several

investigations have found that women who have had a hysterectomy

(cessation of menses) without removal of the ovaries (retained

estrogen) have an increased coronary risk (Gordon, 1978; Palmer,

1992). Nevertheless, estrogen-replacement therapy has been shown to

have favorable effects upon lipoprotein profiles in postmenopausal

women with as much as a 40% reduction in CVD being reported (Green

and Bain, 1993). Stampfer et al. (1991) have reviewed the issue of

estrogen-replacement therapy and heart disease and found that, of 15

prospective studies, 14 found no increased risk of heart disease

among estrogen users. Colditz et al. (1987) also investigated the

association of estrogen and heart disease in a prospective cohort of

121,700 U.S. female nurses. In this study, 14,000 women experienced

natural menopause, and another 8061 reported hysterectomy alone.

After controlling for age and cigarette smoking, women who

experienced natural menopause and who had not received hormone-

replacement therapy had no appreciable increased risk of CHD when

compared with premenopausal women. However, women who had undergone

bilateral oophorectomy (loss of estrogen) and who had never taken

estrogen after menopause had an increased risk. This risk appeared

to be eliminated in women who used estrogen in the postmenopausal

period. Mathews et al. (1989) found that natural menopause had

negative effects on lipid metabolism, indicated by decreases in high-

 

density lipoprotein (HDL) and increases in low-density lipoprotein

(LDL) cholesterol, but women who had received hormone replacement

therapy (estrogen) did not experience any changes in HDL or LDL

cholesterol. Estrogen has been found to exhibit antioxidant activity

by protecting against the cytotoxicity of oxidized LDL by inhibiting

LDL oxidation outside the cell and by enhancing cellular resistance

against oxidized LDL in the cell (Negre-Salvayre et al., 1993).

Estrogen-replacement therapy, either past or present, was strongly

associated with lower LDL-cholesterol, glucose, insulin, fibrinogen,

obesity, and age and higher HDL-cholesterol (Manolio et al., 1993).

Physiological levels of estrogen cause vasodilation of endothelium

in the forearm of postmenopausal women, which may be partly

responsible for the observed long-term effects of estrogen

replacement therapy on cardiovascular incidents in postmenopausal

women (Gilligan et al., 1994). Estrogen's apparent ability to

improve blood cholesterol profiles as well as act as an antioxidant

and vasodilator make it effective in lowering risk of heart disease

in premenopausal women and women using postmenopausal hormone

replacement.

 

Summary

 

There is no question that in certain circumstances the accumulation

of excess iron is possible. In its most severe form,

hemochromatosis, large amount of iron can be deposited in the liver,

spleen and other tissues, causing pronounced impairment in function

and tissue damage. This condition was thought to be rare, and

usually associated with a genetic disorder that results in abnormal

absorption or iron.

 

On the other hand, adequate levels of iron is essential to optimal

health. Iron is difficult to absorb from vegetables, fruits, beans,

whole grains and supplements. Even in the absence of overt anemia,

iron deficiency can produce such symptoms as fatigue, behavioral

problems (decreased alertness and attention span), muscle weakness

and increased susceptibility to infections.17

 

Even if iron-overload is more common than once was thought, the

evidence does not support a blanket recommendation that iron be

completely eliminated from the diet, or from supplementation, for

certain population groups. The average American diet is too poor,

and iron deficiency is too prevelant, to make such a generalization.

 

While there may be a preponderance of anti-iron commentary in

certain areas, it is important to maintain a proper perspective,

especially when looking at epidemiological studies. For example, it

is known that Candida infections of the skin and mucous membranes

are more common in patients who are iron deficient.17 This is true

for herpes simplex infections as well. Certainly, the majority of

those who are outspoken critics of iron supplements are at the same

time aware of what could almost be called a " candida epidemic. " Can

we not then conclude that this epidemic of candida albicans is

related to low iron levels?

 

The same could be said, perhaps, of what we are calling " chronic

fatigue syndrome. " Muscle weakness and decreased exercise tolerance

are frequently associated with iron-deficiency anemia. But these

symptoms can occur even when there is iron deficiency but not anemia

and can be resolved when the iron deficiency is corrected.17

 

And, as pointed out by Dr. Murray, when commenting on the oft-quoted

Finnish Study, " Another way of expressing the results of the study

would be to simply state that Finnish men eating more meat have an

increased risk for heart attacks, elevated LDL-cholesterol levels,

and elevated iron stores. Therefore, the study simply provided

additional evidence that high meat intake increases the risk of

heart attack. This is nothing new; it is just a different way in

which high meat intake can lead to premature death. " 18

 

The same can be said for a more recent report concerning iron

supplements and colorectal cancer. In the recent edition of

Nutrition Science News, (June 1999, Vol.4, No.6) the headline in

their " Natural News " section reads " Extra iron Spawns Free Radicals

in Gut. "

 

The article starts off with the following sentence: " People who take

dietary iron supplements may run an increased risk of colorectal

cancer, suggests recent research that draws a direct correlation

between iron intake and free radical generation. "

 

This is misleading. As they go on to say, " …studies since have found

that people with iron-heavy diets, such as meat eaters, have more

colon cancer. " Again, as Dr. Murray pointed out, this may or may not

be directly related to iron. Other aspects of a heave meat eater's

diet may be responsible for this association with higher rates of

colon cancer.

 

In this particular study,19 what they actually did was look at the

feces of 18 healthy people who supplemented for two weeks with an

additional 19 mg of iron. They collected the feces, and measured

iron levels and free radical production. Since we know that most

iron is not absorbed, it would be expected that the level in the

feces would increase, and it did, along with free radical

production.

 

This free radical increase was measured outside the body, however.

We do not know what significance, if any, this might have inside the

bowel. Nor do we know with any certainty that this iron induced free

radical generation has any significance toward disease. In fact,

interestingly enough, in the same issue of Nutrition Science News,

in an article on probiotics, the author explains that one of the

most important functions of probiotic organisms (acidophilus,

bifidus, etc) to limit the growth of pathogenic organisms. How do

these friendly bacteria do that? They " …secrete substances-lactic

acid and other organic acids, hydrogen peroxide, and potent

antibiotic agents known as bacteriocins-that inhibit the growth of

harmful organisms. " Please note that hydrogen peroxide is a powerful

source of free radical oxygen.

 

So it is important to put reports such as this in proper

perspective. Remember, what we have is a connection between people

with a certain dietary pattern, high meat eaters, and increased risk

of certain diseases. It so happens that high meat intake normally

results in high iron levels. This does not necessarily mean that the

iron is responsible for the disease.

 

A study such as the one reported above, looking at iron intake, and

resultant levels in the feces, can only lead to two conclusions:

First, as we would expect, increased iron intake results in

increased levels of iron in the stool, and second, the increase iron

in the stool, at least in vitro, can lead to increased levels of

free radicals in the stool. If we choose to believe that it is the

iron, rather than other meat- or life-style related factors that

might be responsible for the disease assocated with this group, then

this study provides clues as to what the mechanism might be. But

that is all.

 

Another interesting finding by the authors of the study, by the way,

was that " Higher carbohydrate diets were associated with reduced

free radical generation. "

 

The following conclusion by Proulx, et.al. sums it up quite

nicely: " Although the iron and heart disease hypothesis offers an

intriguing explanation for many of the factors associated with heart

disease, subsequent research has not been supportive of the

paradigm. Confounding variables inherent in the study of eastern

Finnish men (i.e., the presence of serum ferritin levels of 2200

µg/L, the known high level of CAD, high concentration of LDL, and

the potentially atherogenic diet in this population) make definitive

conclusions and extrapolations to other population groups difficult.

However, other factors analyzed in this investigation that were

found to have more substantial relative risks for AMI than ferritin

may be worthy of further investigation. Manttari et al. (1993) found

that there was a linear trend in CHD risk with increasing

ceruloplasmin, the copper transport protein, in dyslipidemic men. In

the Finnish study, serum copper had the highest relative risk of all

factors analyzed. Numerous studies investigating the relationship

between iron and heart disease largely have been unable to support

the findings of the Finnish study and the iron/heart disease

paradigm. On the other hand, research supporting estrogen as the

main factor explaining the difference in rates of heart disease

between men and premenopausal women is convincing. Nevertheless,

when the negative consequences of iron deficiency are considered

along with the prevalence of iron-overload disease, prudent but

timely action on this issue is imperative. Universal screening for

iron storage diseases as recommended by Herbert (1992) seems to be

an efficacious and reasonable approach to the public health problem

of iron overload, because measurements of iron status are relatively

inexpensive and effective treatment is available. Those found to

have levels of iron that would put them at risk for toxicity should

be advised to reduce their iron levels and avoid iron supplements.

Otherwise, until sound scientific evidence indicates differently,

the rest of the general public should be encouraged to consume as

near the RDA for iron for their age and gender as possible. " 11

 

A similar conclusion was arrived at by Corti, et.al. in their 1997

paper: " Free iron, as well as other transition metals, can catalyze

free radical formation. For this reason iron is tightly bound to

transport and storage proteins to prevent their involvement in free

radical formation. It has been hypothesized that increased iron

intake or iron stores may promote atherogenesis by increasing free

radical formation and oxidative stress. While a coherent, plausible

hypothesis as to how transition metals, such as iron, might

accelerate the progression of atherosclerosis has been generated

from basic research, iron status, measured as dietary iron intake,

serum iron, serum ferritin, and transferrin saturatgion, has bee

inconsistently associated with cardiovascular disease in human

epidemiologic research. In addition, limited data suggest that iron

overload states do not appear to be strongly associated with

increased risk of atherosclerotic disease...At present the currently

available data do not support radical changes in dietary

recommendations or screening to detect high normal levles nor do

they support the need for large-scale randomized trials of dietary

restriction or phlebotomy as a means of lowering iron stores. " 20

 

The rational approach

 

Holford, in his book The Optimum Nutrition Bible, discusses the

Finnish Study, and the correlation between blood ferritin levels and

cardiovascular risk. He reports Sullivan's theory that " this might

explain why menstruating women, who lose iron each month, have a

lesser risk of cardiovascular disease than men until after the

menopause. " But he concludes that " This theory is yet to be proven,

but suggests that meat-eating men should not go overboarfd on iron

supplements. In practice, this means limiting the dose to 10 mg a

day.2

 

As Dr. Robert Atkins says, " If both low and high levels of iron can

be bad, then which is worse? Well, by the time you've reached your

seventies the answer is high iron is better, according to a 1997

U.S. government survey of nearly four thousand seniors. Men and

women with the highest serum level had 38 percent and 28 percent

lower all-cause death rates, respectively.3

 

" The toxicity of iron is low, and harmful effects of daily intakes

of up to 75 milligrams per day are unlikely in healthy individuals.

The body has a highly effective mechanism that prevents an overload

of iron from entering it and causing toxicity. The amount of iron

the body absorbs is carefully regulated by the intestines, according

to the body's needs. The greater the need, the higher the rate of

absorption. Growing children, pregnant women, and anemic individuals

have higher rates of absorption. When a deficiency occurs, the rate

of absorption increases to two to three times higher than normal.

(Unfortunately, this response does not appear to be sufficient to

prevent anemia in iron-deficient subjects who are only mildly anemic

and whose iron intake is marginal.)

 

There have been conflicting scientific reports concerning iron and

the risk of coronary heart disease. Some studies have shown that

high iron levels in the blood appear to increase the risk of heart

disease, while other studies have failed to confirm these findings.

Some studies have demonstrated that high levels of serum ferritin (a

complex in which iron is stored in the tissues) or of total iron

binding capacity (TIBC) appear to increase the risk of heart

disease, while other studies have failed to confirm these findings,

as well. What does all this mean?

 

We know that antioxidants are our natural defense against free

radical oxidative stress, and that iron is a very powerful pro-

oxidant-an initiator of oxidative stress. The discrepancies in the

study findings may be the result of the balance of antioxidants and

iron. Even though iron is essential to the functioning of our

bodies, too much iron combined with poor antioxidant defense, due to

poor intake of antioxidants would put anyone at high risk for

increased oxidative stress, which is believed to be a culprit in

heart disease. Since we can easily measure iron, TIBC, and ferritin

levels in our blood, these levels should routinely be screened

during physical exams. If high levels are present, a reduction of

iron intake should be discussed with your physician.

 

In some cases, a dangerous condition known as hemochromatosis can

cause the excessive absorption of iron. This results in a build-up

of excess iron in the tissues of many organs, possibly leading to

damage to the liver, heart, pancreas, and other organs. 1n genetic

hemochromatosis, there is inappropriately high absorption of dietary

iron from birth. Acquired hemochromatosis may occur as a result of

transfusions, medical conditions, or excessive long-term iron

intake, This condition, too, can easily be detected through blood

tests. If the tests confirm the condition, steps should be taken to

avoid iron in food and supplements, and to avoid foods cooked in

cast iron cookware or stored in metal cans. 12

 

In response to the claim that iron promotes oxidation, contributing

to heart disease in men and rheumatoid arthritis, Dr. Saul Hendler

offers the following observation: " That iron can generate free

radicals is well known. Unbound iron in the ferrous (or `plus two')

state is a potent generator of hydroxy radicals, which can be very

destructive to cells. However, unbound iron occurs only under

certain conditions. Patients with hemochromatosis, a genetic

disorder of excessive iron accumulation, can have a significant

quantity of unbound iron in their cells, and this may give rise to

extensive damage to liver, heart, pancrease and skin. These genetic

disorders, however, are rare. And there is no convincing evidence at

present that iron is active in either rheumatoid arthritis or

atherosclerotic disease. Most iron we come in contact with is

tightly bound to protein and does not generate dangerous free

radicals....Prolonged administration or iron supplements very rarely

causes iron overload...Iron supplements are widely used in the

United States, and reports of toxicity from iron overload are very

rare.17

 

And finally, the commentary on this question of iron levels and risk

of heart attack presented by Dr. Michael Murray in his book,

Encyclopedia of Nutritional Supplements, further helps to put the

concern over excess iron into proper perspective:

 

" Recent news accounts highlight the possible relationship of

elevated iron levels and the risk for heart attacks. The articles in

the popular press are based on several scientific studies. However,

the news accounts do not provide all the information. For example,

let's look at the study published in the medical journal

Circulation. In this study of Finnish men, researchers demonstrated

that high stored-iron levels produced by a diet of excess meat is

associated with excess risk of heart attack, Although iron was

singled out, the study also demonstrated an increased risk for a

heart attack when LDL-cholesterol levels were elevated. In other

words, the strongest link between increased stored iron levels and

risk for a heart attack was found in men with LDL-cholesterol levels

greater than 193 milligrams per deciliter. Furthermore, the

strongest dietary link to an increased risk for a heart attack in

the study was meat intake. Meat intake was also linked to increased

LDL-cholesterol levels and increased dietary intake of saturated

fats.

 

Another way of expressing the results of the study would be to

simply state that Finnish men eating more meat have an increased

risk for heart attacks, elevated LDL-cholesterol levels, and

elevated iron stores. Therefore, the study simply provided

additional evidence that high meat intake increases the risk of

heart attack. This is nothing new; it is just a different way in

which high meat intake can lead to premature death.

 

Elevated levels of iron may lead to an increased risk of heart

disease by spinning off free radicals in the blood and either

damaging cholesterol or the artery walls directly. Antioxidants like

vitamin C and vitamin E protect against iron-induced oxidative

damage. " 18

 

Conclusion

 

For people who are not in the high risk group for iron deficiency

(i.e. none of the following: menstruating women, dieters, pregnant

women, endurance athletes, strict vegetarians, infants and

children), it is prudent to moderate or reduce iron supplement

intake. This would include men, especially heavy meat eaters.

 

Some experts indeed claim that " adult men who eat well-balanced

diets of 2,000 calories or more do not need iron supplements.. " 17

This may be true, but the same can be said for all vitamins and

minerals, depending on your viewpoint. The problem, of course, is

that so few of us can claim to eat a well-balanced diet. More

realistic, in my opinion, is to reduce the amount of iron to a more

prudent level.

 

A level of less than 10 mg in a balanced multivitamin would be

appropriate. It is important to utilize a multivitamin with a full

spectrum of antioxidants, to ensure, in addition to all the many

benefits antioxidants provide, that the iron does not function as a

pro-oxidant. An additional antioxidant blend is usually desirable in

any case.

 

Those who feel that they might for any reason be in danger of too

much stored iron should have the appropriate blood tests run to

determine whether or not they have a valid reason for concern. The

proper test for this purpose would be a serum ferritin test, which

measures how much iron is stored in the body.

 

If there is insufficient reason to request a serum ferritin test,

then I suggest that there is insufficient reason to totally

eliminate iron from the daily supplement program. The importance of

adequate iron levels should dictate the inclusion of a moderate

level in the daily supplement program.

 

The realization that genetic iron overload disease is a more common

disorder than was one thought is not to be interpreted as

justification for depriving otherwise healthy adults of the benefits

of iron supplementation. Instead, it should be considered basis for

increased emphasis on blood test screening so that those individuals

can be properly identified.

 

There is no basis for totally restricting iron supplementation in

the absence of such clinical testing. As explained above, the value

of iron is too great to risk a deficiency. While elderly men can be

thought to be more likely to have adequate iron stores, it should be

remembered that elderly men are at the same time more likely to have

difficulty absorbing iron due to reduced levels of hydrochloric acid

in the stomach.

 

It should also be kept in mind that the actual amount of iron

absorbed from a supplement is small. This is especially true when

the supplement contains a large amount of calcium.16 Just as calcium

interferes with the absorption of lead, it interferes with the

absorption of iron.

 

The general rule of thumb, in fact, is that only about 10% of iron

is absorbed. The actual estimated requirement for iron for adult men

is 0.65 to 1.3 mg. This leads to a Recommended Daily Allowance of 10

mg (National Research Council). The Food and Drug Administration, in

adopting the " US RDA " or " Percent Daily Value " for label purposes,

increased the level to 18 mg. A level of 10 mg, therefore, is more

in keeping with the level recommended for men over the age of 19,

and women over the age of 51.

 

For those in the other category, where there is little question but

that there is need additional iron supplementation, an additional

supplement and/or increased dietary heme iron intake is necessary.

This would include, of course, adolescents, premenopausal women,

pregnant and lactating women, those with anemia, dieters, " and the

elderly with poor dietary habits over long periods of time. " 17

 

Special Note: Willvite

 

In the product Willvite, a total multivitamin-multimineral

supplement formulated by Willner Chemists, the amount of iron

present is 9 mg, per four tablets, which represents 50% of

the " Percent Daily Value " as mandated by the FDA. As explained

above, for most people, we feel this represents an appropriate

compromise. In addition, the type of iron used is a form bound to

fumaric acid, the chelated ferrous fumarate. This form, especially

in the presence of a balanced array of antioxidants, is considered

safe and effective. (For iron deficiency, for example, Dr. Michael

Murray18 recommends " iron bound to either succinate or fumarate " ).

 

http://www.willner.com/References/webref36.htm

 

References

 

1. Univ. of California at Berkeley Wellness Letter. The New Wellness

Encyclopedia. Houghton Mifflen Co. 1995.

 

2. Holford, Patrick. The Optimum Nutrition Bible. The Crossing

Press, 1999.

 

http://www.willner.com/References/webref36.htm